Glass Delamination: a Comparison of the Inner Surface Performance of Vials and Pre-filled Syringes

The occurrence of glass delamination is a serious concern for parenteral drug products. Over the past several years, there has been a series of product recalls involving glass delamination in parenteral drugs stored in vials which has led to heightened industry and regulatory scrutiny. In this study, a two-pronged approach was employed to assess the inner surface durability of vials and pre-filled syringes. Non-siliconized syringes were used in order to directly compare glass to glass performance between vials and syringes. The vial and syringe performance was screened with pharmaceutically relevant formulation conditions. The influence of pH, buffer type, ionic strength, and glass type and source was evaluated. In addition, an aggressive but discriminating formulation condition (glutaric acid, pH 11) was used to ascertain the impact of syringe processing. Advanced analytical tools including inductively coupled plasma/mass spectrometry, scanning electron microscopy, atomic force microscopy, and dynamic secondary ion mass spectroscopy showed significant differences in glass performance between vials and syringes. Pre-filled syringes outperform vials for most tests and conditions. The manufacturing conditions for vials lead to glass defects, not found in pre-filled syringes, which result in a less chemically resistant surface. The screening methodology presented in this work can be applied to assess suitability of primary containers for specific drug applications.Key words: borosilicate vials, glass delamination, glass corrosion, hydrolytic resistance, pre-filled syringes     

An economical system for liquid scintillation counting

Small glass shell vials (12 × 35 mm minivials), containing 2.0 ml of a dioxane-based scintillation solution plus a ¹⁴C-labeled sample, were placed in a conventional glass, 20-ml count vial and assayed in a scintillation spectrometer. Statistical comparison of counts recorded from ¹⁴C samples prepared both in the minivial system and conventional 20-ml count vials indicated that the two systems were equivalent with sample volumes of 10 and 100 μliters (1600-cpm solution) and 10 μliters (60-cpm solution). Conventional 20-ml glass or plastic count vials were both acceptable as containers for the minivials.There were no significant differences in the counts from samples in minivials placed on-center and off-center in the container vial. Cost per sample was reduced from 24.8 cents (conventional glass vials) to 4.7 cents (minivial system).     

Protection of histones isolated from elastase-treated mouse epidermis

Small glass shell vials (12 × 35 mm minivials), containing 2.0 ml of a dioxane-based scintillation solution plus a ¹⁴C-labeled sample, were placed in a conventional glass, 20-ml count vial and assayed in a scintillation spectrometer. Statistical comparison of counts recorded from ¹⁴C samples prepared both in the minivial system and conventional 20-ml count vials indicated that the two systems were equivalent with sample volumes of 10 and 100 μliters (1600-cpm solution) and 10 μliters (60-cpm solution). Conventional 20-ml glass or plastic count vials were both acceptable as containers for the minivials.There were no significant differences in the counts from samples in minivials placed on-center and off-center in the container vial. Cost per sample was reduced from 24.8 cents (conventional glass vials) to 4.7 cents (minivial system).     

The effect of sample composition and vial type on Ĉerenkov counting in a liquid scintillation counter

The effect of sample vial type and sample composition on the ?erenkov count rate detected from ³²P and ³⁶Cl was studied using a liquid scintillation counter. When counting was done in the noncoincident mode, glass vials allowed higher counting efficiency than plastic vials. In the coincident mode light scattering caused by polyethylene and polyproplyene vials allowed higher counting efficiency than glass vials. Highest coincident counting efficiency was from plastic minivials in a glass carrier vial. Increased solute concentration in samples caused increased counting efficiency due to changes in the refractive index of the solution. This can cause significant counting efficiency changes with no sample channel ratio change in density gradient fractions. The use of wavelength shifters is shown to be inappropriate when the sample pH varies, as this can change the fluorescent properties of the shifters and thereby the observed count rate.     

Substantial progress made in the rearing of the European cherry fruit fly, Rhagoletis cerasi

We examined phenyl propionate as an attractant for trapping navel orangeworm, Amyelois transitella (Walker) (Lepidoptera: Pyralidae) adults, with the objective of developing a method of trapping both sexes more effectively than with almond meal. Two initial experiments maximized the total number of adults captured using phenyl propionate released from glass vials with cotton wicks. A third experiment compared the numbers of males and females captured using these glass dispensers in either bucket or sticky traps. The glass vial dispensers captured more adults than 0.1% phenyl propionate in water (as both attractant and killing agent), and far more adults were captured with glass vial phenyl propionate dispensers than with almond meal. On rare occasion, the glass vial dispensers captured as many adults as traps baited with virgin females, but usually phenyl propionate in glass vials captured fewer adults than virgin‐baited traps. Glass vial phenyl propionate dispensers were equally effective in sticky traps or bucket traps. The majority of females captured were mated, and the proportion of males captured increased over time within flights (generations). We conclude that phenyl propionate released from glass vials captured A. transitella adults more effectively than currently available options, and will be useful in research projects where capturing intact adults and comparing mating status are important. Developing a cost‐effective phenyl propionate‐based alternative to the egg traps currently used for commercial monitoring will be more difficult.     

Ethylene loss from the gas phase of container-seal systems

Ethylene losses from the gas phase of various container-seal systems were studied to develop acceptable methods for containing ethylene during experiments. Ethylene at an initial amount of 104 μI I^-1 was stored in glass vials at near atmospheric pressure for 20 h at 25–27°C and at 35% relative humidity external to the vials. Crimped serum vials sealed with saturated (NH₄)₂SO₄ solution, neoprene rubber septa, nitrile rubber (Hycar) septa, butyl rubber septa, and brown translucent silicone rubber septa lost ethylene at the rate of 1.8, 10.2, 16.2, 16.5, and 40.2 nl m^-2s^-1, respectively, over the 20-h period. Screw-capped reaction vials sealed with white silicone rubber septa lost ethylene at the rate of 30.2 nl m^-2s^-1. The (NH4)₂SO₄ solution was utilized as a seal by inverting a vial so that the salt solution covered the internal surface of the vial septum. Saturated (NH₄)²SO₄ solution is an effective seal. Silicone rubber should be avoided as a seal in systems for containing ethylene. Ethylene production values in the literature may be underestimates where silicone rubber seals have been used.     

Factors Affecting the Use of Impedance Spectroscopy in the Characterisation of the Freezing Stage of the Lyophilisation Process: the Impact of Liquid Fill Height in Relation to Electrode Geometry

This study aims to investigate the application of impedance spectroscopy using fixed electrode geometries on a standard glass vial in the characterisation of the freezing process of solutions at different fill liquid volumes. Impedance spectra (between 10 and 10⁶ Hz) were recorded every 3 min, during the freezing cycle on a solution of 30 mg/mL sucrose contained within 10 mL glass vials having an electrode system (two thin copper foils: w, 18 mm; h, 5 mm) affixed to the external surface of the vial. A fill factor (Φ) was defined in terms of the relative height of the solution volume to the height of the electrodes from the base of the vial. Solution volumes of 1.5 to 5 mL (corresponding to Φ= 0.5–1.6) were investigated to establish the applicability of having a fixed electrode geometry for a range of solution volumes. A linear relationship between the time duration of the ice formation/solidification phase and the fill factor suggests that fixed electrode geometries may be used to investigate a range of fill volumes. The benefit of this approach is that it does not invade the solution and hence records the freezing process without providing additional nucleation sites and in a manner which is representative of the entire fill volume.KEY WORDS: fill height, freezing, impedance spectroscopy, sucrose     

Loss of vacuum in rubber stoppered vials stored in a liquid nitrogen vapor phase freezer

A total of 1885 rubber stoppered 3-ml vials (NS-33 and NS-51 glass (expansion sizes), sealed under vacuum, were subjected to the ultracold temperatures of a liquid nitrogen vapor phase (LNVP) freezer for 16.5 hr and tested for vacuum loss after equilibration back to 25 °C. The presence of a vacuum in each vial was checked before and after freezing. Results with two lots of vials per glass expansion size showed positive or no negative pressure rather than a vacuum in 46.25% (NS-33), 98.25% (NS-33), 64.72% (NS-51), and 99.38% (NS-51) of the vials. Apparently, the fit or slight misfit of the stopper into the vial opening and the hardness of the butyl rubber stopper at ultracold temperatures enhance the chances of leakage around the stopper area under extremely cold temperatures. Storage of rubber stoppered vials containing lyophilized products sealed under vacuum in LNVP freezers is not advisable.     

Behavioral and reproductive responses of female opossums to volatile and nonvolatile components of male suprasternal gland secretion

Female gray short-tailed opossums (Monodelphis domestica) lack an estrous cycle and are induced into estrus by exposure to a pheromone in male scent marks. Behavioral and physiological responses of females to the volatile and nonvolatile components of scent marks were examined in two experiments. Young females (n = 9) were tested prior to and during their first estrus for behavioral responses to scent marks, collected on a 7-ml glass vial rubbed over the suprasternal gland of a mature male. The response to volatile components of the scent mark, recorded when marked and unmarked vials were covered with a perforated shield, was compared to the response to these vials when unshielded. Estrous females nuzzled the shields over marked vials (55.8 ± 8.5 nuzzles/10 min) more than the shielded clean vial (10.9 ± 2.4) (P < 0.05); a similar response was observed in anestrous females. Nuzzling of unshielded, scent-marked vials was higher (P < 0.05) during anestrus than in the same females when in estrus. The role of nonvolatile pheromones in reproductive activation was tested in adult females (n = 11) exposed for up to 14 days to a shielded, marked vial or to an unshielded, marked vial in a crossover design. All females exposed to unshielded vials expressed estrus, and 10 copulated. Only 2 females expressed estrus (significantly fewer, P < 0.05), when exposed to shielded marked vials, and neither copulated. These results demonstrate that females detect and respond behaviorally to both volatile and nonvolatile components of male suprasternal gland secretion, but the estrus-inducing pheromone in these secretions is nonvolatile.     

Argentine ant (Hymenoptera: Formicidae) trail pheromone enhances consumption of liquid sucrose solution

We investigated whether the Argentine ant, Linepithema humile (Mayr), trail pheromone, Z9-16:Ald, could enhance recruitment to and consumption of liquid sucrose solutions. All tests were done as paired comparisons with a 10% sucrose solution as food. In the laboratory, mixing 20 microl of a 10-microg/ml solution of the pheromone with 50 microl of the 10% sucrose solution increased the number of ants feeding by >150%. In a field test, we combined the trail pheromone with a 10% sucrose solution in 50-ml vials. These vials were covered with a plastic membrane that has 1.5-mm-diameter holes punched uniformly across its surface. Ants could drink from the holes after the vials were inverted. For half of the vials, 1 microg of the pheromone was put onto the plastic membrane before the vials were filled with a 10% sucrose solution. The remaining vials had no pheromone on the plastic membrane. After 4 h we measured the consumption in each vial. Bait consumption with the pheromone was enhanced by 29%. In a 2nd series of tests, vials were left outside for 24 h. The consumption rate was 33% higher with the pheromone compared with the controls that didn't have pheromone.     

Development of a Mini-Freeze Dryer for Material-Sparing Laboratory Processing with Representative Product Temperature History

The goal of the work described in this publication was to evaluate a new, small, material-sparing freeze dryer, denoted as the “mini-freeze dryer or mini-FD”, capable of reproducing the product temperature history of larger freeze dryers, thereby facilitating scale-up. The mini-FD wall temperatures can be controlled to mimic loading procedures and dryer process characteristics of larger dryers. The mini-FD is equipped with a tunable diode laser absorption spectroscopy (TDLAS) water vapor mass flow monitor and with other advanced process analytical technology (PAT) sensors. Drying experiments were performed to demonstrate scalability to larger freeze dryers, including the determination of vial heat transfer coefficients, K _v . Product temperature histories during K _v runs were evaluated and compared with those obtained with a commercial laboratory-scale freeze dryer (LyoStar II) for sucrose and mannitol product formulations. When the mini-FD wall temperature was set at the LyoStar II band temperature (? 20°C) to mimic lab dryer edge vials, edge vial drying in the mini-FD possessed an average K _v within 5% of those obtained during drying in the LyoStar II. When the wall temperature of the mini-FD was set equal to the central vial product temperature, edge vials behaved as center vials, possessing a K _v value within 5% of those measured in the LyoStar II. During both K _v runs and complete product freeze drying runs, the temperature-time profiles for the average edge vials and central vial in the mini-FD agreed well with the average edge and average central vials of the LyoStar II.     

Behavioral and reproductive responses of female opossums to volatile and nonvolatile components of male suprasternal gland secretion

Female gray short-tailed opossums (Monodelphis domestica) lack an estrous cycle and are induced into estrus by exposure to a pheromone in male scent marks. Behavioral and physiological responses of females to the volatile and nonvolatile components of scent marks were examined in two experiments. Young females (n = 9) were tested prior to and during their first estrus for behavioral responses to scent marks, collected on a 7-ml glass vial rubbed over the suprasternal gland of a mature male. The response to volatile components of the scent mark, recorded when marked and unmarked vials were covered with a perforated shield, was compared to the response to these vials when unshielded. Estrous females nuzzled the shields over marked vials (55.8 ± 8.5 nuzzles/10 min) more than the shielded clean vial (10.9 ± 2.4) (P < 0.05); a similar response was observed in anestrous females. Nuzzling of unshielded, scent-marked vials was higher (P < 0.05) during anestrus than in the same females when in estrus. The role of nonvolatile pheromones in reproductive activation was tested in adult females (n = 11) exposed for up to 14 days to a shielded, marked vial or to an unshielded, marked vial in a crossover design. All females exposed to unshielded vials expressed estrus, and 10 copulated. Only 2 females expressed estrus (significantly fewer, P < 0.05), when exposed to shielded marked vials, and neither copulated. These results demonstrate that females detect and respond behaviorally to both volatile and nonvolatile components of male suprasternal gland secretion, but the estrus-inducing pheromone in these secretions is nonvolatile.     

The Effect of Container Surface Passivation on Aggregation of Intravenous Immunoglobulin Induced by Mechanical Shock

Aggregation of therapeutic proteins can result from a number of stress conditions encountered during their manufacture, transportation, and storage. This work shows the effects of two interrelated sources of protein aggregation: the chemistry and structure of the surface of the container in which the protein is stored, and mechanical shocks that may result from handling of the formulation. How different mechanical stress conditions (dropping, tumbling, and agitation) and container surface passivation affect the stability of solutions of intravenous immunoglobulin are investigated. Application of mechanical shock causes cavitation to occur in the protein solution, followed by bubble collapse and the formation of high‐velocity fluid microjets that impinged on container surfaces, leading to particle formation. Cavitation was observed after dropping of vials from heights as low as 5 cm, but polyethylene glycol (PEG) grafting provided temporary protection against drop‐induced cavitation. PEG treatment of the vial surface reduced the formation of protein aggregates after repeated dropping events, most likely by reducing protein adsorption to container surfaces. These studies enable the development of new coatings and surface chemistries that can reduce the particulate formation induced by surface adsorption and/or mechanical shock.     

Heat and mass transfer scale-up issues during freeze-drying,I: Atypical radiation and the edge vial effect

The aim of this study is to determine whether radiation heat transfer is responsible for the position dependence of heat transfer known as the edge vial effect. Freeze drying was performed on a laboratory-scale freeze dryer using pure water with vials that were fully stoppered but had precision cut metal tubes inserted in them to ensure uniformity in resistance to vapor flow. Sublimation rates were determined gravimetrically. Vials were sputter-coated with gold and placed at selected positions on the shelf. Average sublimation rates were determined for vials located at the front, side, and center of an array of vials. Sublimation rates were also determined with and without the use of aluminum foil as a radiation shield. The effect of the guardrail material and its contribution to the edge vial effect by conduction heat transfer was studied by replacing the stainless steel band with a low-thermal conductivity material (styrofoam). The emissivities (ε) of relevant surfaces were measured using an infrared thermometer. Sublimation rate experiments were also conducted with vials suspended off the shelf to study the role of convection heat transfer. It was found that sublimation rates were significantly higher for vials located in the front compared to vials in the center. Additional radiation shields in the form of aluminum foil on the inside door resulted in a decrease in sublimation rates for the front vials and to a lesser extent, the center vials. There was a significant decrease in sublimation rate for goldcoated vials (ε≈0.4) placed at the front of an array when compared to that of clear vials (ε≈0.9). In the case of experiments with vials suspended off the shelf, the heat transfer coefficient was found to be independent of chamber pressure, indicating that pure convection plays no significant role in heat transfer. Higher sublimation rates were observed when the steel band was used instead of Styrofoam while the highest sublimation rates were obtained in the absence of the guardrail, indicating that the metal band can act as a thermal shield but also transmits some heat from the shelf via conduction and radiation. Atypical radiation heat transfer is responsible for higher sublimation rates for vials located at the front and side of an array. However, the guardrail contributes a little to heat transfer by conduction.     

Surface transformation of bioactive glass in bioreactors simulating microgravity conditions. Part II: numerical simulations

The effects of simulated microgravity on the surface modification of bioactive glass (BG) in solution were studied using a numerical method. Models were developed for estimating the mass transfers of different chemical species from the surface of bioactive glass particles (microcarriers) suspended in the rotating liquid medium of a NASA-designed high aspect ratio vessel (HARV) bioreactor and on the bottom surface of a static vial. The concentration profiles resulting from chemical reactions and ionic transports were ascertained. Numerical results for the transport under simulated microgravity in the HARV and at normal gravity in the static vial were compared. These results were also compared with those of experiments to verify the enhancement of the reaction kinetics under simulated microgravity conditions. The experimental and numerical studies confirm that simulated microgravity conditions lead to the quick achievement of bioactive glass surface modification.     

A SIMPLE TUMBLING DEVICE USED IN PREPARING ALGAL SPECIMENS FOR ELECTRON MICROSCOPY

Screw cap vials are held in a wooden holder which rotates at a 90° angle to the horizontal. The. shaft of a small electric motor with built-in gear box is attached perpendicularly to the wooden vial holder via a hole drilled in the center of the wooden holder. The rotation of the vial holder is about 6 rpm. This motion ensures a thorough tumbling of the contents of the vials. Even viscous embedding media are kept in constant agitation, which provides for superior penetration of the tissue. Tumbling devices to hold a range of vial sizes can be constructed with a minimum of labor at a cost of $10–20 each.     

Impact of Natural Variations in Freeze-Drying Parameters on Product Temperature History: Application of Quasi Steady-State Heat and Mass Transfer and Simple Statistics

Inter- and intra-batch variability in heat and mass transfer during the drying phase of lyophilization is well recognized. Heat transfer variability between individual vials in the same batch arise from both different positions in the vial array and from variations in the bottom contour of the vials, both effects contributing roughly equally to variations in the effective heat transfer coefficient of the vials, K_v. Both effects can be measured in the laboratory, and variations in average K_v values as a function of vial position in the array for lab and production can be calculated by use of the simple steady-state heat and mass transfer theory. Typically, in the laboratory dryer, vials on the edge of the array, “edge vials,” run 2–4°C warmer than “center vials,” but differences between laboratory and manufacturing temperatures are modest. The variability in mass transfer can be assigned to major variations in ice nucleation temperature (both intra-batch and inter-batch), including major differences between laboratory and manufacturing. The net effect of all random variations, for each class of vial, can be evaluated by a simple statistical model-propagation of error, which then allows prediction of the distribution in product temperatures and drying times, and therefore prediction of percent of vials dry and percent of vials collapsed and proximity to the edge of failure for a given process. Good agreement between theoretical and experimentally determined maximum temperatures in primary drying and percent collapsed product demonstrates the calculations have useful accuracy.     

Increased Parasitization of Aphids on Trap Plants Alongside Vials Releasing Synthetic Aphid Sex Pheromone and Effective Range of the Pheromone

Aphid-infested cereal trap plants were used to detect the effects of aphid sex pheromone components on aphid parasitoid activity in arable field margins. The presence of aphid sex pheromones significantly increased parasitization levels by aphid parasitoids on the plants. By placing plants alongside and at varying distances away from a pheromone-releasing vial, the technique was used to measure the distance over which a point source of aphid sex pheromone could increase parasitization levels. Pheromone-releasing vials significantly increased parasitization by the generalist parasitoid Praon volucre on plants adjacent to vials and on plants placed 20 cm away. When the distance between pheromone-releasing vials and aphid-infested plants was increased to 1 m, parasitization by P. volucre was increased only on the plant adjacent to the vial, whereas parasitization by the specialist parasitoid Aphidius rhopalosiphi was also increased on plants placed 1 m away. This indicates a possible difference between the parasitoids in their foraging behaviour in response to semiochemical cues during host selection. When the experiment was repeated with some trap plants placed 3 m away from the pheromone-releasing vial, parasitization was again concentrated on plants directly alongside the vial, but only P. volucre appeared to be active in the field at the time of this experiment, so the effect on A. rhopalosiphi could not be assessed. The results are encouraging for the prospects of using aphid sex pheromones to manipulate parasitoids in order to improve aphid population control.     

Fully automated solid weighing workstation

A fully automated, solid-to-solid weighing workstation (patent pending) is described in this article. The core of this automated process is the use of an electrostatically charged pipette tip to attract solid particles on its outside surface. The particles were then dislodged into a 1.2-mL destination vial in a microbalance by spinning the pipette tip. Textures of solid that could be weighed included powder, crystalline, liquid, and semi-solid substances. The workstation can pick up submilligram quantities of sample (=0.3mg) from source vials containing as little as 1mg. The destination vials containing the samples were stored in a 96-well rack to enable subsequent automated liquid handling. Using bovine serum albumin as test solid, the coefficient of variation of the protein concentration for 48 samples is less than 6%. The workstation was used successfully to weigh out 48 different synthetic compounds. Time required for automated weighing was similar to manual weighing. The use of this workstation reduced 90% hands-on time and thus exposure to potentially toxic compounds. In addition, it minimized sample waste and reduced artifacts due to the poor solubility of compound in solvents. Moreover, it enabled compounds synthesized in milligram quantities to be weighed out and tested in biological assays.     

Problem in liquid scintillation counting: adsorption of (14-C)pholyethylene glycol in dilute solutions.

[¹⁴C]polyethylene glycol is the method of choice for quantitating changes in intestinal water flux during drug absorption experiments in animals and man. This study points out some of the problems which can be encountered in using this method and provides ways to minimize these problems. Polyethylene glycol selectively binds to the glass wall of scintillation vials during counting and results in a decrease in counting efficiency as a function of time. The results obtained when using this method are determined by the choice of scintillation vial, scintillation cocktail, concentration of polyethylene glycol and the time period over which the samples are counted.